Gynecologic Cancers Bradley J. Monk, M.D. Associate Professor - - PowerPoint PPT Presentation

Gynecologic Cancers

Bradley J. Monk, M.D.

Associate Professor Division of Gynecologic Oncology Chao Family Comprehensive Cancer Center University of California Irvine Medical Center Orange CA USA 92868

2

• n behalf of MRC and EORTC collaborators; Mount Vernon Cancer Centre, Middlesex,

United Kingdom; Erasmus MC University Medical Center, Rotterdam, Netherlands

A randomized trial in ovarian cancer (OC) of early treatment of relapse based on CA125 level alone versus delayed treatment based

• n conventional clinical indicators

(MRC OV05/EORTC 55955 trials)

• G. J. Rustin, M. E. van der Burg

J Clin Oncol 27:15s, 2009 (suppl; abstr 1)

Ovarian Carcinoma: CA-125

• Serum glycoprotein (OC-

125)

• Discovered during a

search to boost an immunotherapy (Corynebacterium parvum)[1]

• Blood test introduced in

1981 – Elevated in 82% of

• varian cancers; 1% in

controls[2]

• CA-125 cloned in 2001[3]

– Mapped to chromosome 19 (p13.3) – Gene: MUC16 – Very large molecule

• 1. Bast RC, et al. J Clin Invest. 1981;68:1331-1337. 2. Bast RC, et al. N Engl J Med. 1983;309:883-887.
• 3. Yin BW, et al. J Biol Chem. 2001;276:27371-27375.

Trial Profile

Registered patients N=1442

Randomised N=529 (37%)

Delayed treatment

N=264 N=233 (88%) started second-line chemotherapy

Early treatment

N=265 N=254 (96%) started second-line chemotherapy

Non randomised patients

N (%) 421 (29) CA125<2ULN and no relapse at trial closure 61 (4) Simultaneous relapse and CA125>2ULN 213 (15) Relapsed without CA125>2ULN 56 (4) Died 133 (9) Patient withdrawal 29 (2) Other/unknown reasons

Baseline characteristics: All randomised patients (N=529)

Early Delayed Age Median (range) 60 (35-86) 61 (37-93) FIGO stage I II III IV 9% 11% 68% 12% 8% 10% 69% 13% WHO PS 1 2 & 3 69% 29% 2% 75% 25% <1% Histology Serous Endometroid Mucinous Clear cell Undifferentiated Adenocarcinoma not otherwise specified Other 66% 12% 3% 4% 8% 6% 1% 59% 12% 3% 4% 6% 15% 1%

Second-line chemotherapy

Regimen administered Early N (%) Delayed N (%) Single agent platinum Combination platinum (no taxane) Platinum + taxane based Taxane without platinum Other Unknown treatment No treatment given Not yet given (no clinical relapse) 78 (29) 40 (15) 91 (34) 15 (6) 28 (11) 2 (1) 11 (4) 67 (25) 33 (13) 101 (38) 9 (3) 15 (6) 8 (3) 24 (9) 7 (3) Total 265 264

0.00 0.25 0.50 0.75 1.00 Proportion alive not started second-line chemotherapy

264 177 116 91 69 56 49 42 33 Delayed 265 23 16 14 11 11 10 10 9 Early

Number at risk 3 6 9 12 15 18 21 24 Months since randomisation

Time from randomisation to second-line chemotherapy

Median (months) Early 0.8 Delayed 5.6 HR=0.29 (95% CI 0.24, 0.35) p<0.00001

0.00 0.25 0.50 0.75 1.00

Proportion surviving

264 236 203 167 129 103 69 53 38 31 19 Delayed 265 247 211 165 131 94 72 51 38 31 22 Early

Number at risk 6 12 18 24 30 36 42 48 54 60

Months since randomisation

Overall Survival

HR=1.00 (95%CI 0.82-1.22) p=0.98

Early Delayed Abs diff at 2 years= -0.1% (95% CI diff= -6.8, 6.3%)

Time from randomisation to first deterioration in Global Health Score (or death)

0.00 0.25 0.50 0.75 1.00 Proportion alive without deterioration in GHS

194 93 55 38 25 Delayed 190 68 44 23 12 Early

Number at risk 6 12 18 24 Months since randomisation Median (months) Early 3.1 Delayed 5.8 HR=0.71 (95% CI 0.57, 0.87) p=0.001

• In early treatment arm based on rise of CA125

– Second-line chemotherapy started a median of 4.8 months earlier – Third-line chemotherapy started a median of 4.6 months earlier

• This early treatment did not improve overall survival
• HR=1.00, 95% CI 0.82-1.22, p=0.98
• Absolute difference at 2 years -0.1% (95%CI -6.8,

6.3%)

• Early chemotherapy does not improve Qol

Conclusions

June, 2009: SGO Statement on Use of CA125 for Monitoring Ovarian Cancer

• Role of secondary cytoreduction not addressed
• Not stratified for residual disease after cytoreduction
• Remission not confirmed by imaging
• Treatment at relapse not standardized
• “Patients and their physicians should still have the
• pportunity to choose [CA125 monitoring] as a

philosophy of active management that includes participation in trials of novel therapies”

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The David Geffen School of Medicine at UCLA, Los Angeles, CA; Santa Clara Valley Medical Center, San Jose, CA; Cedars-Sinai Medical Center, Los Angeles, CA

Influence of residual disease and extreme drug resistance assays on

• utcome in patients with epithelial
• varian cancer
• A. Karam, J. Wang Chiang, E. Fung, V. Nossov, B. Y. Karlan

J Clin Oncol 27:15s, 2009 (suppl; abstr 5504)

Kern and Weisenthal, JNCI 1990

Kern and Weisenthal, JNCI 1990

Aims and Methods

• Aims:

– Effects of EDR assay-guided therapy in epithelial Ovarian Cancer (EOC) – Outcomes in the primary and recurrent setting

• Retrospective review

– 377 EOC patients at Cedars Sinai Medical Center, Los Angeles – EDR assays between 1995 and 2005

• End points

– Time to first recurrence (TTP) – Overall survival (OS) – Survival after recurrence (RS)

Demographic and Clinical Characteristics

Variable Frequency Percent Age, years Median (Range) 59.0 (24.4-89.1) Race White 315 87.7 Non-white 44 12.3 Residual Disease at 1° CRS Microscopic 76 29.9 0.1-1 cm 145 57.1 ≥1 cm 33 13.0 FIGO Stage I/II 34 10.2 III/IV 300 89.8 Tumor Grade 1 11 3.9 2 14 4.9 3 260 91.2 Histology Papillary Serous 265 77.9 Other 75 22.1

Variable Frequency Percent Primary Chemotherapy Platinum and taxane 231 88.8 Platinum based 25 10.7 Other 4 1.5 2° CRS No 93 36.0 Yes 165 64.0 Recurrence type Platinum resistant 75 29.4 Platinum sensitive 180 70.6 Residual Disease at 2° CRS Microscopic 63 42.6 0.1-1 cm 55 37.2 ≥1 cm 30 20.3 Status NED 85 22.8 AWD 28 7.5 DOD 251 67.3 DOC 9 2.4

Adjuvant Therapy and Recurrence

EDR assay results Frequency Percent EDR Assay at 1° CRS No 125 36.5 Yes 217 63.5 N EDR Assays 1 292 85.4 ≥2 50 14.6 EDR assay results Carboplatin EDR 57 18.2 Cisplatin EDR 52 15.8 Cyclophosphamide EDR 85 26.1 Taxol EDR 51 15.7 Platinum EDR 81 23.1 Taxane EDR 58 17.2 Platinum + taxane EDR 15 4.5

EDR Assay Results

Multivariate Analysis

Multivariate Disease progression Death Characteristic HR 95% CI p HR 95% CI p Age decades 1.12 0.98 1.28 0.1 1.33 1.13 1.56 0.001 Stage Stage <III 1.0 1.0 Stage ≥III 3.61 0.86 6.4 0.09 2.78 0.68 11.3 0.15 Tumor grade Grade 1 1.0 1.0 Grade 2 or 3 1.87 0.68 5.14 0.23 5.41 0.73 40.1 0.10 1° CRS residual Microscopic 1.00 1.00 0.1 to 1.0 cm 1.94 1.33 2.84 0.001 1.59 1.03 2.45 0.04 >1.0 cm 3.61 2.07 6.29 <0.001 2.14 1.09 4.20 0.03 Adjuvant chemotherapy Platinum and taxane 1.00 Other 0.94 0.23 3.86 0.93 EDR assay None 1.0 At primary surgery 1.13 0.75 1.72 0.55

CRS=Cytoreductive Surgery

Multivariate Analysis

Multivariate Death after recurrence Characteristic HR 95% CI p 2° CRS residual disease Microscopic 1.0 0.1 to 1.0 cm 1.14 0.74 1.77 0.55 >1.0 cm 2.84 1.71 4.71 <0.001 No 2° CRS 2.13 1.28 3.54 0.004 Initial PFS <6 months 1.00 6 to 12 months 1.15 0.75 1.76 0.52 12 to 24 months 1.32 0.83 2.08 0.24 >24 months 1.25 0.84 1.86 0.28 EDR assay None 1.0 At recurrence 0.83 0.55 1.27 0.40

CRS=Cytoreductive Surgery

Conclusion

• EDR did not predict outcomes in EOC

patients

• Age and disease residual important for
• utcome
• Rationale for assays remains strong

– Continued research – Gene-expression/microarray profiles

Limitations and Strengths

• Limitations:

– Retrospective nature – Selection and ascertainment bias – Incomplete information on salvage chemotherapy

• Strengths:

– Size of patient population – Treated with platinum and taxane chemotherapy – Long follow-up (median ~5 years)

Odense University Hospital, Odense, Denmark; University of Tuebingen, Tuebingen, Germany; Centre Hospitalier , La Roche sur Yon, France; Philipps University, Marburg, Germany; The Norwegian Radium Hospital, Oslo, Norway; University Hospital Ulm, Ulm, Germany; Ubbo-Emmius-Klinik gGmbH, Aurich, Germany; St. Vincentius-Krankenhäuser, Karlsruhe, Germany; Centre Léon Bérard, Lyon, France; HSK, Dr. Horst Schmidt Klinik GmbH, Wiesbaden, Germany

A randomized, phase III study (AGO-OVAR-9, GINECO-TCG, NSGO-OC- 0102): Gemcitabine-paclitaxel-carboplatin (TCG) versus paclitaxel-carboplatin (TC) as first-line treatment of ovarian cancer (OC): Survival of FIGO stage I-IIA patients

• J. Herrstedt, J. Huober, F. Priou, H. Müller, M.

Baekelandt, C. Kurzeder, J. Pfisterer, A. Stähle,

• I. Ray-Coquard, A. du Bois

J Clin Oncol 27:15s, 2009 (suppl; abstr LBA5510)

GOG 182—Primary Therapy

FIGO III-IV All residuum EOC or PPC International Paclitaxel 175 mg/m2 3 hours Carboplatin AUC 5 mg/mL•min Paclitaxel 175 mg/m2 3 hours Carboplatin AUC 5 mg/mL•min Gemcitabine 800 mg/m2 days 1, 8 Paclitaxel 175 mg/m2 3 hours Carboplatin AUC 5 mg/mL•min PLD 30 mg/m2 ALTERNATING COURSES Paclitaxel 175 mg/m2 3 hours Carboplatin AUC 6 mg/mL•min,

x4 cycles

Topotecan 1.5 mg/m2 days 1 - 3 Carboplatin AUC 5 mg/mL•min,

x4 cycles

Paclitaxel 175 mg/m2 3 hours Carboplatin AUC 6 mg/mL•min, x4 cycles Gemcitabine 1,000 mg/m2 days 1, 8 Carboplatin AUC 6 mg/mL•min,

x4 cycles

THEN THEN Paclitaxel 175 mg/m2 3 hours Carboplatin AUC 6 mg/mL•min All regimens = 8 cycles Interval cytoreduction allowed No second-look surgery Endpoints: PFI, survival, response N > 4,000 patients

PFI = Progression-free interval; FIGO =International Federation of Gynecologic Oncologists; EOC = Epithelial ovarian cancer; PPC = Primary peritoneal cancer; AUC = Area under the concentration-time curve.

GOG0182-ICON5: Progression-Free

Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.838-1.141) 16.4 0.998 (0.832-1.136) 15.3 1.094 (0.918-1.244) 15.4 1.052 (0.888-1.206) Bookman ASCO Abstract # 5002 2006; J Clin Oncol. 2009 Mar 20;27(9):1419-25.

GOG0182-ICON5: Overall Survival

Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman ASCO Abstract # 5002 2006; J Clin Oncol. 2009 Mar 20;27(9):1419-25.

R A N D O M I S A T I O N q 21 x 6

Paclitaxel 175 mg/m² d1 Carboplatin AUC 5 d1

q 21 x 6

Gemcitabine 800 mg/m² d1+8 Paclitaxel 175 mg/m² d1 Carboplatin AUC 5 d1

STUDY DESIGN

0,25 0,5 0,75 1 6 1 2 1 8 24 30 36 42 48 54 60 66 72

PROGRESSION-FREE SURVIVAL (RECIST & CA125) BY THERAPY: STRATUM 2+3 (FIGO IIB-IV)

[months]

793 699 511 351 270 225 191 152 95 43 14 2 774 685 483 307 228 185 155 116 72 36 12 2 Patients at risk

HR = 1.17 [95% CI: 1.05-1.31]

Logrank test: p = 0.0065

TC 793 pts. / 588 evts. median 16.0 [14.9-17.4] mos. TCG 774 pts. / 629 evts. median 14.7 [14.0-15.9] mos.

OVERALL SURVIVAL BY THERAPY STRATUM 2+3 (FIGO IIB-IV)

0,5 1 6 1 2 1 8 24 30 36 42 48 54 60 66 72 78

TC 793 pts. / 401 evts. median 48.9 [43.1-51.2] mos. TCG 774 pts. / 404 evts. median 45.8 [40.0-49.5] mos. HR = 1.03 [95% CI: 0.90-1.18] p = 0.6955

793 750 705 638 557 489 420 338 226 89 31 5 774 740 693 628 554 484 411 322 208 87 28 5

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Istituto Nazionale Tumori , Napoli, Italy; Università Cattolica del Sacro Cuore, Roma, Italy; Istituto Regina Elena, Roma, Italy; CRO, Aviano, Italy; Ospedale Fatebenefratelli, Isola Tiberina, Roma, Italy; Casa di Cura La Maddalena, Università di Palermo, Palermo, Italy; Ospedale Oncologico M.Ascoli A.R.N.A.S., Palermo, Italy; Seconda Università di Napoli, Napoli, Italy; Istituto Nazionale Tumori di Napoli, Napoli, Italy

Carboplatin plus paclitaxel (CP) versus carboplatin plus stealth liposomal doxorubicin (CLD) in patients with advanced ovarian cancer (AOC): Activity and safety results of the MITO-2 randomized multicenter trial

Pignata, G. Scambia, A. Savarese, R. Sorio, E. Breda, G. Ferrandina, V. Gebbia, P. Musso, C. Gallo, F. Perrone

J Clin Oncol 27:15s, 2009 (suppl; abstr LBA5508)

Study population

Inclusion criteria

• Cyto/histological diagnosis of ovarian cancer
• FIGO Stage IC – II – III – IV
• Age  75
• ECOG Performance Status 0-2
• No previous chemotherapy

Main exclusion criteria

• ANC  2000/L, platelets  100000/L
• Creatinine  1.25 x UNL, SGOT and SGPT  1.25 x UNL
• Life expectancy of less than 3 months

R a n d

• m

Strata:

• Center
• PS (0-1, 2)
• Stage (IC, II, III, IV)
• Residual disease after surgery

(absent, 1 cm, 1 cm, no surgery)

Control arm

Carboplatin AUC 5, day 1 Paclitaxel 175 mg/m2, day 1 Treatment repeated every 21 days, for 6 cycles

Experimental arm

1:1

Study design

Carboplatin AUC 5, day 1 PLD 30 mg/m2, day 1 Treatment repeated every 21 days, for 6 cycles

Activity analysis: flow of patients

Analysis performed according to “intention to treat” principle

Pending information

Eligible for RECIST

Not eligible for RECIST Non-target lesions only Elevated CA-125 only No lesions, normal CA-125 Carbo + Paclitaxel (n=410) 10 pts 83 pts 88 pts 73 pts

156 (38%)

18 pts 99 pts 80 pts 79 pts

134 (33%)

Carbo + PLD (n=410)

Objective response – RECIST Women with target lesions

Carbo + Paclitaxel (n=156) Carbo + PLD (n=134) p (2)*

Objective response 92 (59%) 76 (57%) 0.70 Complete response 24 (15%) 22 (16%) Partial response 68 (44%) 54 (40%) No response 64 (41%) 58 (43%) Stable disease 45 (29%) 41 (31%) Progressive disease 9 (6%) 7 (5%) Not evaluated 10 (6%) 10 (7%) *Objective response vs no response

Toxicity (1)

Any grade Severe (G3)

C+P C+PLD p* C+P C+PLD p*

Toxic deaths 0.8% 0.5% 1 Anemia 59% 68% 0.007 4% 10% 0.001 RBC transfusions 2% 6% 0.002 Neutropenia 73% 80% 0.04 49% 43% 0.09 Febrile neutropenia 2% 1% 0.21 Thrombocytopenia 19% 48% 0.001 2% 16% 0.001 Platelet transfusions 0.3% 2% 0.06 Bleeding 0.3% 1% 0.37

• 1%

0.24

C+P: carboplatin + paclitaxel, 399 patients; C+PLD: carboplatin + PLD, 386 patients *Chi square or Fisher exact test as appropriate

Toxicity (2)

Any grade Severe (G3)

C+P C+PLD p* C+P C+PLD p* Allergy 6% 5% 0.60 2% 2% 0.86 Heart 2% 4% 0.26 0.3% 2% 0.06 Fatigue 44% 43% 0.86 3% 3% 0.94 Constipation 32% 32% 0.99 1% 1% 0.73 Nausea 47% 51% 0.21 2% 2% 0.95 Vomiting 29% 30% 0.83 2% 3% 0.42 Diarrhoea 13% 6% 0.001 1%

• 0.25

Hair loss 63% 14% 0.001 Skin toxicity 6% 20% 0.001

• 2%

0.01 Stomatitis 9% 20% 0.001 0.3% 0.5% 0.62 Neurotoxicity 47% 15% 0.001 3% 0.2% 0.004

*Chi square or Fisher exact test as appropriate C+P: carboplatin + paclitaxel, 399 patients; C+PLD: carboplatin + PLD, 386 patients

Preliminary conclusions (1)

• Toxicity profile of carboplatin plus PLD as first-line

treatment of advanced ovarian cancer is markedly different from carboplatin plus paclitaxel

• Carboplatin plus PLD is associated with:

– Higher incidence of anemia and thrombocytopenia (rarely requiring transfusions) – Higher incidence of stomatitis and cutaneous toxicity (that are rarely severe) – Lower incidence of hair loss and neurotoxicity

Preliminary conclusions (2)

• There was no statistically significant difference in

response rate between carboplatin plus PLD and carboplatin plus paclitaxel

• Final analysis for the primary endpoint (PFS) will

be performed as soon as the required number of events will be reached

40

GINECO, Paris, France; AGO-OVAR, Hamburg, Germany; NSGO, Oslo, Norway; ANZGOG, Sydney, Australia; NCIC Clinical Trials Group, Vancouver, BC, Canada; ANZGOG, Queensland, Australia; AGO-Austria, Vienna, Austria; EORTC, Leuven, Belgium; MITO, Napoli, Italy; MANGO, Torino, Italy

A randomized, phase III study of carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in relapsed platinum-sensitive

• varian cancer (OC): CALYPSO study of the

Gynecologic Cancer Intergroup (GCIG)

• E. Pujade-Lauraine, S. Mahner, J. Kaern, V. Gebski,
• M. Heywood, P. Vasey, A. Reinthaller, I. Vergote,
• S. Pignata, A. Ferrero

J Clin Oncol 27:15s, 2009 (suppl; abstr LBA5509)

CALYPSO Study Schema

Ovarian cancer in late relapse (> 6 months) after 1st- or 2nd-line platinum-based therapy (previous taxane required) International, Intergroup, Open-label, Randomized Phase III Study

Stratification:

• Therapy-free interval

(6-12 mo vs > 12 mo)

• Measurable disease

(yes vs no)

• Center

R A N D O M I Z E

Experimental arm: CD PLD 30 mg/m2 IV d 1 Carboplatin AUC 5 d 1 Control arm: CP Paclitaxel 175 mg/m2 IV d 1 Carboplatin AUC 5 d 1 Q 28 days x 6 courses* Q 21 days x 6 courses*

*or progression in patients with SD or PR

Baseline Characteristics (1)

Characteristic CD (n=466) CP (n=508) Number of patients (%) Age, median ECOG performance status* 1 2 Primary site of disease Ovarian Papillary/Serous histology FIGO stage* I/II III IV Size of residual disease* ≤ 1 cm > 1 cm 60.5 286 (61) 159 (34) 13 (3) 415 (89) 334 (72) 52 (11) 339 (73) 62 (13) 251 (54) 129 (28) 61.0 317 (62) 164 (32) 15 (3) 451 (89) 366 (72) 59 (12) 373 (73) 54 (11) 262 (52) 129 (26)

* Missing values to attain 100%.

Baseline Characteristics (2)

Characteristic CD (n=466) CP (n=508) Number of patients (%) Number of previous lines One Two Prior taxane Interval since prior therapy, median 6-12 months > 12 months Measurable disease Yes No 408 (88) 58 (12) 462 (99) 162 (35) 304 (65) 330 (71) 136 (29) 421 (83) 87 (17) 500 (99) 182 (36) 326 (64) 370 (73) 138 (27)

Early Treatment Discontinuation

Reason CD (n=466) CP (n=501) Number of patients (% of total) Toxicity* Patient/investigator choice Progressive disease Intercurrent disease TOTAL* 27 (6) 16 (3) 26 (6) 1 (<1) 70 (15) 73 (15) 14 (3) 22 (4) 1 (<1) 110 (22)

* P< 0.001

Hematologic Toxicity

Toxicity, grade(gr) CD (n=464) CP (n=500) P Value Number of patients (%) Neutropenia, gr 3 gr 4 144 (31) 20 (4) 121 (24) 108 (22) <0.01 Febrile Neutropenia, gr 3-4 10 (2) 21 (4) NS Infection, gr 3-4 11 (3) 14 (3) NS Thrombocytopenia, gr 3-4 73 (16) 31 (6) <0.01 Bleeding, gr 3-4 3 (0.6) 0 (0) NS Anemia, gr 3-4 37 (8) 27 (5) NS

NS=not significant.

Overall Non-Hematologic Safety Profile

Overall non- hematologic toxicity CD (n=465) CP (n=498) P Value Number of patients (%) Grade 0-1 72 (15) 14 (3) <0.01 Grade 2 257 (55) 298 (59) Grade 3-5 136 (29) 189 (38) Severe Adverse Event 64 93 0.034

Selected Non-Hematologic Toxicities During Treatment

CD (n=466) CP (n=501) Grade 2 Grade 3/5 Grade 2 Grade 3/5 Hypersensitivity* 3% 2% 10% 9% Treatment partially stopped

• 4%

Study treatment stopped 1% 4%

Hypersensitivity Reactions

*P< 0.001 Protocol included EORTC guidelines for re-challenge after a hypersensitivity reaction to carboplatin

Selected Non-Hematologic Toxicities During Treatment

CD (n=466) CP (n=501) Grade 2 Grade3/ 4 Grade 2 Grade 3/4 Nausea/vomiting* 31% 4% 20% 4% Constipation 19% 2% 20% 2% Diarrhea 4% 2% 6% 2% Arthralgia/myalgia* 4% 0% 18% 1% Hand-foot syndrome* 11% 2% 2% 0% Mucositis* 13% 2% 6% 1% Cardiac disorders 2% 1% 3% 1%

*P< 0.001

Selected Non-Hematologic Toxicities During Treatment

CD (n=466) CP (n=501) Alopecia grade 2* 7% 84%

Alopecia

*P< 0.001

Long-Lasting Toxicities

CD (n=466) CP (n=501) Grade 2 Grade 3/5 Grade 2 Grade 3/5 Fatigue 31% 7% 34% 7% Neuropathy* 4% 1% 24% 4%

*P< 0.001 Long-Lasting Neuropathy

Progression-Free Survival (ITT)

Carbo- PLD Carbo- pacli Median PFS, mo 11.3 9.4 HR (95% CI) 0.82 (0.72, 0.94) Log-rank p-value (superiority) 0.005 P-value (non-inferiority) <0.001

52

University of Texas M. D. Anderson Cancer Center, Houston, TX; GOG Statistical and Data Center, Buffalo, NY; Oklahoma University Health Science Center, Oklahoma City, OK; Columbus Cancer Council, Columbus, OH; University of Minnesota, Minneapolis, MN

Sentinel node (SN) biopsy in patients with vulvar cancer: A Gynecologic Oncology Group (GOG) study.

• C. F. Levenback, C. Tian, R. L. Coleman,
• M. A. Gold, J. M. Fowler, P. L. Judson

J Clin Oncol 27:15s, 2009 (suppl; abstr 5505)

Lymphedema

Excellent Target for SLNB Concept

Conclusions

• Future GOG studies should include SLNB in the

management of patients with early vulvar cancer – FNPV < 5% – Sensitivity >88%

• SLNB is best limited to patients with tumors < 4 cm
• The combined technique is recommended

56

Unidad de Investigacion Biomédica en Cáncer, Mexico City, Mexico; Medical Centre San Roque, Tucuman, Argentina; National Institute of Oncology, Panama, Panama; Siriraj Hospital, Bangkok, Thailand; Institute of Oncology, Sarajevo, Bosnia and Herzegovina; Postgraduate Institute of Medical Education and Research, Chandigarh, India; National Institute of Oncology, Lima, Peru; Eli Lilly and Company, Sydney, Australia; Eli Lilly Interamerica, Buenos Aires, Argentina

A phase III study comparing concurrent gemcitabine (Gem) plus cisplatin (Cis) and radiation followed by adjuvant Gem plus Cis versus concurrent Cis and radiation in patients with stage IIB to IVA carcinoma of the cervix

A.Dueñas-González, J. J. Zarba, J. C. Alcedo, P. Pattarunataporn, S. Beslija, F. Patel, L. Casanova, B.H. Barraclough, M. Orlando

J Clin Oncol 27:15s, 2009 (suppl; abstr CRA5507 )

Study Design

Week 0 Weeks 1 to 6 Week 7 Weeks 8 to 9 Weeks 10 to 15

Randomization Chemoradiation BCT Adjuvant Chemotherapy Arm A 2 cycles of: cisplatin 50 mg/m2 (day 1) + gemcitabine 1 g/m2 (days 1 and 8) given q3 weeks Stratified by: stage; tumor size; investigator site; radiation equipment (Co60 or LinAc); age N=515 patients Arm A N=259 cisplatin 40 mg/m2 + gemcitabine 125 mg/m2 weekly for 6 weeks pelvic EBRT 50.4 Gy 1.8 Gy/day in 5.4 weeks Arm B N=256 cisplatin 40 mg/m2 weekly for 6 weeks pelvic EBRT 50.4 Gy 1.8 Gy/day in 5.4 weeks 30-35 Gy (low or IM DR)

REST

30-35 Gy (low or IM DR)

Patient baseline characteristics

Abbreviations: N = total number of patients; n = number of patients per category. P-values determined by (e) Fisher‟s exact test or (t) t test.

Characteristic Arm A N=259 Arm B N=256 Overall N=515 p-value

Age, years Median (range) 45.0 (22 – 68) 46.0 (18 – 70) 46.0 (18 – 70) 0.377 (t) Karnofsky Performance Status Median (range) 90.0 (80 – 100) 90.0 (70 – 100) 90.0 (70 – 100) 0.734 (t) Pathological Diagnosis, n (%) Adenocarcinoma Non-adenocarcinoma 17 (6.6) 242 (93.4) 15 (5.9) 241 (94.1) 32 (6.2) 483 (93.8) 0.856 (e) Stage of Disease, n (%) IIB IIIA IIIB IVA 160 (61.8) 1 (0.4) 94 (36.3) 4 (1.5) 156 (60.9) 1 (0.4) 94 (36.7) 5 (2.0) 316 (61.4) 2 (0.4) 188 (36.5) 9 (1.7) 0.973 (e) Maximum Diameter of the Largest Lesion, cm Median (range) 6.00 (2.0 – 20.0) 5.90 (2.8 – 11.0) 6.00 (2.0 – 20.0) 0.494 (t) Hemoglobin at Baseline, g/dL Median (range) 12.00 (7.9 – 15.8) 12.05 (8.5 – 15.9) 12.00 (7.9 – 15.9) 0.893 (t) Country, n (%) Bosnia Pakistan Thailand Argentina Panama Peru India Mexico 33 (12.7) 27 (10.4) 34 (13.1) 17 (6.6) 31 (12.0) 29 (11.2) 60 (23.2) 28 (10.8) 28 (10.9) 29 (11.3) 33 (12.9) 18 (7.0) 30 (11.7) 31 (12.1) 56 (21.9) 31 (12.1) 61 (11.8) 56 (10.9) 67 (13.0) 35 (6.8) 61 (11.8) 60 (11.7) 116 (22.5) 59 (11.5) 0.997 (e)

Enrolment: 10 sites, 8 countries (May „02 to March ‟04) - follow-up completed April ‟08.

months 6 12 18 24 30 36 42 48 54 60 PFS probability 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Log-rank p=0.023 Hazard ratio = 0.68 95% CI = 0.49-0.95

Gem/cis/rad Cis/rad

Progression-Free Survival at 3 Years

PFS at 3 years: 74.4% in Gem/cis/rad versus 65.0% in Cis/rad (p=0.029)

Abbreviations: CI = confidence interval; cis = cisplatin; Gem = gemcitabine; PFS = progression-free survival; Rad = radiation.

months 6 12 18 24 30 36 42 48 54 60 PFS probability 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Gem/cis/rad Cis/rad

Overall Survival

OS was statistically superior for Gem/cis/rad over Cis/rad OS at 3 years: 78.2% in Gem/cis/rad versus 69.1% in Cis/rad months

6 12 18 24 30 36 42 48 54 60 66

OS probability

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Log-rank p = 0.022 Hazard ratio = 0.68 95% CI = 0.49-0.95

Gem/cis/rad Cis/rad

Abbreviations: CI = confidence interval; cis = cisplatin; Gem = gemcitabine; OS = overall survival; Rad = radiation.

Overall Study Drug-Related Toxicity

Drug-related CTCAE Grade 3/4 toxicity (on-study or within 30 days of last study drug dose) Arm A N=260 Grade 3 (%) Grade 4 (%) Arm B N=255 Grade 3 (%) Grade 4 (%) p-value Neutropenia 45.0 6.2 5.1 0.8 <0.001 Anemia 7.7 1.5 1.6 0.4 <0.001 Thrombocytopenia 5.4 0.8 1.2 0.0 0.004 Febrile neutropenia 1.5 0.8 0.4 0.0 0.123 Diarrhea 17.7 0.0 4.7 0.0 <0.001 Nausea 3.8 0.4 2.7 0.0 0.473 Vomiting 7.7 0.0 2.4 0.4 0.016 Fatigue 3.1 0.8 1.6 0.0 0.174 Radiation dermatitis 11.2 0.0 10.6 0.0 0.888 Abdominal pain/cramping 2.7 0.0 0.4 0.0 0.068 Anorexia 0.4 0.0 0.0 0.0 1.000 Proctitis 2.7 0.8 0.4 0.0 0.020 AST 0.8 0.0 0.0 0.0 0.499 ALT 0.8 0.0 0.0 0.0 0.499 Creatinine 1.5 0.0 0.4 0.4 0.686 Other*

Abbreviations: ALT = alanine aminotransaminase; AST = aspartate aminotransaminase; CTCAE = Common Toxicity Criteria Adverse Event; N = total number of patients. * Other = low incidence of toxicity overall or for Grade 3/4 – also includes toxicities deemed not to be clinically significant.

Late Toxicity

Arm A (N=260) Arm B (N=255) Maximum toxicity score Maximum toxicity score 3 4 3 4 Toxicity N* n (%) n (%) N* n (%) n (%) p-value** Any 222 1 (0.5) 8 (3.6) 216 1 (0.5) 2 (0.9) 0.176 (e) Skin 211 0 (0.0) 0 (0.0) 207 0 (0.0) 0 (0.0) 0.730 (e) SC tissue 210 1 (0.5) 0 (0.0) 206 0 (0.0) 0 (0.0) 0.646 (e) Mucous membrane 210 0 (0.0) 1 (0.5) 208 0 (0.0) 1 (0.5) 0.450 (e) Spinal cord 207 0 (0.0) 0 (0.0) 204 0 (0.0) 0 (0.0) 0.857 (e) Small/large intestine 213 0 (0.0) 5 (2.3) 209 1 (0.5) 0 (0.0) 0.044 (e) Bladder 209 0 (0.0) 3 (1.4) 204 0 (0.0) 1 (0.5) 0.067 (e)

Abbreviations: SC = subcutaneous; N = total number of patients; n = number of patients within category. Because of rounding, not all percentages add up to 100. Late toxicity measured using Radiotherapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria. *Some data were missing. This table includes only toxicities occurring more than 30 days after last study drug dose. ** Comparison was for incidence of toxicity of all severities. (e) Fisher‟s exact test.

Conclusions

• When compared with the current standard of care, inclusion of

gemcitabine significantly improves survival outcomes for patients with locally advanced cervical cancer at the expense of increased, but clinically acceptable and manageable, toxicity

• Further studies are required to define the optimal application of this

regimen and to delineate the relative contributions of multi-agent chemoradiation and adjuvant chemotherapy to survival outcomes and toxicity

ASCO 2009 Gyn Cancer Summary

• Ovarian Cancer

– CA125 surveillance questioned – EDR assay not validated – First-line IV carboplatin + paclitaxel still standard – First-line IV Carboplatin + PLD (or + Gem ASCO 2008) encouraging RR with unique toxicities, PFS and OS pending – Second-line carboplatin + PLD improves PFS compared to carboplatin + paclitaxel, OS pending

• Vulvar Cancer

– Sentinel node biopsies with combined technique if tumor <4cm confrimed

• Locally Advanced Cervical Cancer

– RT + cisplatin + Gemcitabine may be better than RT + cisplatin